Project Summary/Abstract The immune system provides a critical defense against life-threatening infections, but with this capability of robust immune responses comes the risk of immune dysfunction that can itself cause life- threatening diseases. Failure of T cell homeostasis occurs when T cell proliferation, senescence, and/or death are dysregulated, and this leads to diseases including lymphoproliferative disease, lymphopenia, aplastic anemia, and autoimmunity, among others. The phosphoinositide 3-kinase (PI3K) signaling pathway is an important pathway to understand in T cell homeostasis and function since it plays a prominent role in promoting cell growth, changes in metabolism, and proliferation in response to growth factors and mitogens. We have recently described patients with severe immune dysregulation caused by hyperactive PI3K signaling in leukocytes. These patients suffer from immunodeficiency and lymphoproliferative disease caused by heterozygous, gain-of-function mutations in the leukocyte-restricted p110? PI3K. T cells from these patients show (1) defective proliferative responses, which mechanistically link to PI3K-driven terminal differentiation, telomere shortening, and senescence, and (2) increased susceptibility to TCR restimulation-induced cell death, which we hypothesize is due to augmented pro-apoptotic signaling through PKC. Using the valuable resource of these patient T cells together with in vivo mouse models, the overall goal of this proposal is to investigate the role of PI3K signaling in CD8 T cell senescence (Aim 1) and death (Aim 2). The results of these investigations will enable a better understanding PI3K signaling in immune dysregulation that will aid in reaching the long-term goal of devising superior clinical approaches to immunomodulation for immunodeficiencies, lymphoproliferative diseases, lymphopenia, transplantation, and autoimmunity. Furthermore, completing the proposed career development plan as I address these scientific aims will provide a solid foundation for launching a successful career as an independent investigator.